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Zoledronic Acid Versus Placebo in the Treatment of Skeletal
Metastases in Patients With Lung Cancer and Other Solid
Tumors: A Phase III, Double-Blind, Randomized Trial—The
Zoledronic Acid Lung Cancer and Other Solid Tumors
Study Group
By Lee S. Rosen, David Gordon, Simon Tchekmedyian, Ronald Yanagihara, Vera Hirsh, M. Krzakowski, M. Pawlicki,
Paul de Souza, Ming Zheng, Gladys Urbanowitz, Dirk Reitsma, and John J. Seaman
Purpose: To assess the efficacy and safety of zoledronic
acid in patients with bone metastases secondary to solid
tumors other than breast or prostate cancer.
Patients and Methods: Patients were randomly assigned
to receive zoledronic acid (4 or 8 mg) or placebo every 3
weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group).
The primary efficacy analysis was proportion of patients
with at least one skeletal-related event (SRE), defined as
pathologic fracture, spinal cord compression, radiation
therapy to bone, and surgery to bone. Secondary analyses
(time to first SRE, skeletal morbidity rate, and multiple event
analysis) counted hypercalcemia as an SRE.
Results: Among 773 patients with bone metastases from
lung cancer or other solid tumors, the proportion with an
SRE was reduced in both zoledronic acid groups compared
with the placebo group (38% for 4 mg and 35% for 8/4 mg
zoledronic acid v 44% for the placebo group; P ⴝ .127 and
P ⴝ .023 for 4-mg and 8/4-mg groups, respectively). Additionally, 4 mg zoledronic acid significantly increased time to
first event (median, 230 v 163 days for placebo; P ⴝ .023),
an important end point in this poor-prognosis population,
and significantly reduced the risk of developing skeletal
events by multiple event analysis (hazard ratio ⴝ 0.732; P ⴝ
.017). Zoledronic acid was well tolerated; the most common
adverse events in all treatment groups included bone pain,
nausea, anemia, and vomiting.
Conclusion: Zoledronic acid (4 mg infused over 15 minutes) is the first bisphosphonate to reduce skeletal complications in patients with bone metastases from solid tumors
other than breast and prostate cancer.
J Clin Oncol 21:3150-3157. © 2003 by American
Society of Clinical Oncology.
T HAS been estimated that approximately 30% to 65% of
patients with metastatic lung cancer will develop bone
metastases,1,2 and median survival from the time patients develop bone metastases is less than 6 months.2 Bone metastases
cause considerable skeletal morbidity, including bone pain,
pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM).1 These skeletal-related events
(SREs) are the result of the resorption of mineralized bone by
osteoclasts. Bisphosphonates have been used extensively in the
treatment of HCM and in the prevention or palliation of skeletal
complications associated with osteolytic lesions in breast cancer
and multiple myeloma. However, studies in patients with other
solid tumors have been limited.
Zoledronic acid (ZOMETA; Novartis Pharma AG, Basel,
Switzerland/Novartis Pharmaceuticals Corporation, East Hanover,
NJ) is a new, highly potent, nitrogen-containing bisphosphonate that
has demonstrated superior efficacy for the treatment of HCM
compared with pamidronate, the current standard treatment.3
Recently, it has been reported that zoledronic acid offers
greater convenience and is as effective and well tolerated as
pamidronate in the treatment of bone metastases from breast
cancer or multiple myeloma.4,5 Zoledronic acid has also
demonstrated activity in the treatment of bone metastases in
patients with advanced prostate cancer.6
Despite improvements in the primary treatment of lung cancer
and other solid tumors, SREs continue to complicate the clinical
course for many patients. However, the efficacy of bisphosphonates for the treatment of bone metastases in this population has
not been demonstrated in well-controlled trials. Therefore, a
phase III, multicenter, randomized, placebo-controlled trial was
initiated to investigate the effectiveness of zoledronic acid in the
treatment of patients with bone metastases secondary to solid
tumors other than breast or prostate cancer.
I
From the Cancer Institute Medical Group, Santa Monica; Pacific Shores
Medical Group, Long Beach; and Gilroy, CA. US Oncology, San Antonio,
TX. McGill Department of Oncology, Montreal, Quebec, Canada. The M.
Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology,
Warsaw; and Klinika Chemotherapii Centrum Onkologii, Krakow, Poland.
St George Hospital Cancer Care Center, Kogarah, Australia. Novartis
Pharmaceuticals Corp, East Hanover, NJ.
Submitted April 16, 2002; accepted June 4, 2003.
Address reprint requests to Lee S. Rosen, MD, Cancer Institute Medical
Group, 11818 Wilshire Blvd, Suite 200, Los Angeles, CA 90025; email:
[email protected].
© 2003 by American Society of Clinical Oncology.
0732-183X/03/2116-3150/$20.00
3150
PATIENTS AND METHODS
Patients
Adult patients (ⱖ18 years of age) with bone metastases secondary to lung
cancer and other solid tumors not including breast or prostate cancer were
eligible. All patients were required to have at least one site of bone metastasis
Journal of Clinical Oncology, Vol 21, No 16 (August 15), 2003: pp 3150-3157
DOI: 10.1200/JCO.2003.04.105
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ZOLEDRONIC ACID FOR BONE METASTASES
and an Eastern Cooperative Oncology Group (ECOG) performance status
ⱕ 2. Patients were excluded if they had liver metastases with total bilirubin
level higher than 2.5 mg/dL at screening, serum creatinine level higher than
3.0 mg/dL, or symptomatic brain metastases. Patients were also excluded if
they had more than a single exposure to a bisphosphonate within 30 days, a
diagnosis of severe cardiovascular disease, hypertension refractory to treatment, symptomatic coronary artery disease, or pregnancy within 6 months of
random assignment. The study was approved by the institutional review
boards of the respective institutions and was conducted in compliance with
international guidelines regulating patient safety. All patients provided
written informed consent.
Treatment
Patients were randomly assigned in a double-blind fashion to receive
zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months. Initially,
patients received zoledronic acid via 5-minute infusion in 50 mL of infusate;
however, due to concerns over renal safety, a protocol amendment in June
1999 changed the infusion time to 15 minutes and increased the volume of
the infusion to 100 mL (195 patients were accrued before this amendment).
A subsequent amendment to the protocol in June 2000, implemented because
of concerns over decreased renal tolerability at the higher dose level,
required patients originally randomly assigned to receive 8 mg zoledronic
acid to instead receive 4 mg zoledronic acid; this arm is hereafter referred to
as the 8/4-mg arm. All patients were accrued before this amendment, and 198
patients (75%) in the 8/4-mg group had completed or discontinued study
treatment and received only the 8-mg dose; however, 67 patients (25%) were still
receiving treatment and were switched to the lower dose. Thereafter, serum
creatinine was monitored within 2 weeks before each subsequent dose of the
study drug. All patients received daily calcium supplements (500 mg) and a
multivitamin tablet containing vitamin D (400 to 500 U) throughout the study.
Study Design and Schedule
To ensure adequate enrollment of patients with tumor types other than
non–small-cell lung cancer (NSCLC), patients were stratified according to
tumor type (NSCLC or other solid tumor) before random assignment.
Before the first study treatment, a complete physical examination was
performed, and a medical history was taken, which included history of SREs,
antineoplastic history, and ECOG performance status. Tumor assessment,
bone scan, and bone survey were performed before treatment. Pain was
assessed using the Brief Pain Inventory (BPI) composite pain score7 and an
analgesic score (measured on a scale of 0 to 4). Tumor assessment, bone scan
and survey, and ECOG performance status were assessed at 3, 6, and 9
months. Skeletal-related events and adverse events were recorded at each
visit every 3 weeks. Pain and analgesic scores were assessed every 6 weeks.
Statistical Analysis
The primary efficacy analysis was the proportion of patients with at least
one SRE during the 9 months on study. Skeletal-related events included
pathologic fracture, spinal cord compression, radiation therapy to bone, or
surgery to bone. HCM was not included in the definition of SREs for
purposes of the primary efficacy analysis, because the efficacy of zoledronic
acid in the treatment of HCM has been established.3 However, because HCM
is a clinically important event, secondary efficacy analyses are reported with
and without HCM as a skeletal event to evaluate the overall benefit of
zoledronic acid. For all efficacy variables analyzed, comparisons of 4 mg
zoledronic acid versus placebo were used to assess the effectiveness of
zoledronic acid. Therefore, all efficacy conclusions are based on the
recommended 4-mg dose of zoledronic acid. The proportion of patients with
an SRE was compared between treatment groups using the Cochran-MantelHaenszel test stratified by lung cancer and other solid tumors.
Secondary efficacy analyses of SREs included time to first SRE, the
skeletal morbidity rate (defined as the number of SREs per year), and a
multiple event analysis. A preplanned multiple event analysis was performed
using the Andersen-Gill method,8 and the robust estimate of variance was
used to compute P values. For the skeletal morbidity rate and multiple event
analysis, a 21-day event window was used for counting SREs, such that any
event occurring within 21 days of a previous event was not counted. This
ensured that potentially interdependent events, such as surgery to repair a
fracture, occurring within 21 days of a previous event were not counted as
separate SREs. Other secondary efficacy variables included change from
baseline in BPI composite pain score, analgesic use, ECOG performance
status, best bone lesion response, time to progression of bone lesions,
changes from baseline in biochemical markers of bone resorption, time to
progression of overall disease, and survival. Quality of life was measured
using the Function Assessment of Cancer Therapy – General (FACT-G)
instrument, and analyzed using a random effect pattern mixture model.
Time to first SRE, time to progression of bone metastases, time to overall
disease progression, and overall survival were compared between treatment
groups using the Kaplan-Meier method and the log-rank test. For time to first
SRE and progression of bone lesions, a patient who discontinued the study
treatment (including discontinuation due to death) without an event was
censored at the time of discontinuation. For time to progression of overall
disease, death due to progression of disease was counted as an event.
Skeletal morbidity rate and change from baseline in analgesic use,
performance status, and biochemical markers of bone resorption were
compared between treatment groups using the Cochran-Mantel-Haenszel test
stratified by lung cancer and other solid tumors. The mean change from
baseline BPI composite pain score was compared between treatment groups
using analysis of covariance, with baseline value as a covariate, and
treatment and stratum as factors. Time to first serum creatinine increase was
analyzed using the Kaplan-Meier and log-rank tests.
The study was designed to have 80% power to detect a 16% difference in
the proportion of patients having an SRE during the first 9 months of the
study (assuming a 48% incidence of SREs in the placebo group and a 32%
incidence in either zoledronic acid group). Taking into account the variance
included in the intent-to-treat patient population, with an overall type I error
rate of 0.05 (two-sided), the sample size was determined to be 600 patients.
However, because the cumulating blinded data indicated that many patients
died without experiencing an SRE and the overall event rate was lower than
expected, the protocol was amended to enroll 700 patients in the study, to
have 80% power to detect a 14% difference in the proportion of patients
having an SRE (assuming a 38% incidence of SREs in the placebo group and
24% incidence in either zoledronic acid group). There was no interim
analysis and no blinding was broken during the course of amendment. A data
safety monitoring board and a renal safety board were involved in the review
of the data to ensure safe and appropriate study conduct.
RESULTS
Patients
A total of 773 patients with osteolytic, osteoblastic, or mixed
bone metastases from solid tumors other than breast or prostate
cancer were enrolled in the study. As indicated in Table 1, 257
patients were randomly assigned to receive 4 mg zoledronic acid,
266 to receive 8/4 mg zoledronic acid, and 250 to receive
placebo. A total of seven patients did not receive study medication for a variety of reasons, such as errors in issuing randomization numbers. These patients were included in the intent-totreat efficacy analyses but not in the safety analyses because they
did not receive treatment. Approximately 25% of patients
completed 9 months of therapy, and the median duration of
treatment was 4 months. Reasons for discontinuation are presented in Table 1.
Patient and baseline disease characteristics for the assessable
patients are shown in Table 2. Approximately 50% of patients
had NSCLC, 10% of patients had renal cell carcinoma, and 8%
of patients had small-cell lung cancer. Median age was approximately 63 years. The majority (approximately 80%) of patients
3152
ROSEN ET AL
Table 1.
Patient Disposition by Treatment Group
Zoledronic Acid 4 mg
Criterion
Randomized
Assessable for safety
Completed
Discontinued
Reasons for discontinuation
Death
Adverse event(s)
Patient withdrew consent
Insufficient efficacy
Protocol violation
No longer required study drug
Lost to follow-up
Administrative problems
No. of
Patients
%
No. of
Patients
257
254
68
186
—
—
27
73
66
49
44
18
4
2
2
1
26
19
17
7
2
1
1
⬍1
were being treated with chemotherapy and had an ECOG
performance status of ⱕ 1. In all treatment groups, the median
baseline BPI composite pain score was approximately 3.3, and
approximately 90% of patients had normal serum creatinine
levels (⬍1.4 mg/dL) at baseline. Approximately two thirds of the
patients had experienced an SRE before study entry.
Table 2.
Zoledronic Acid 8/4 mg
Median age, years
Sex
Male
Female
Type of cancer
NSCLC
SCLC
Renal cell carcinoma
Cancer unknown primary
Head and neck
Thyroid
Other
Primary therapy
Chemotherapy
Hormonal therapy
Median time from initial diagnosis, months*
ECOG performance status
ⱕ1
ⱖ2
Median BPI composite pain score
Previous SRE
Yes
No
Baseline serum creatinine
Normal (⬍ 1.4 mg/dL)
Abnormal (ⱖ 1.4 mg/dL)
%
%
266
265
65
200
—
—
25
75
250
247
63
184
—
—
25
75
75
65
35
14
0
1
4
1
28
25
13
5
0
⬍1
2
⬍1
66
51
40
20
0
4
0
1
27
21
16
8
0
2
0
⬍1
SREs
The primary end point, which excluded HCM, did not reach
statistical significance for comparison of 4 mg zoledronic acid
versus placebo (38% v 44%; P ⫽ .127), but it was statistically
significant for the comparison of 8/4 mg zoledronic acid versus
placebo (35% v 44%; P ⫽ .023). However, in the analysis of all
Patient and Baseline Disease Characteristics by Treatment Group
Zoledronic Acid 4 mg
(n ⫽ 254)
Characteristic
Placebo
No. of
Patients
No. of
Patients
%
Zoledronic Acid 8/4 mg
(n ⫽ 265)
No. of
Patients
64
%
Placebo
(n ⫽ 247)
No. of
Patients
62
%
64
158
96
62
38
186
79
70
30
159
88
64
36
124
17
27
18
6
2
60
49
7
11
7
2
1
24
134
22
28
16
7
5
53
51
8
11
6
3
2
20
120
19
19
17
4
4
64
49
8
8
7
2
2
26
207
3
82
1
212
1
80
⬍1
197
2
80
1
3.8
211
42
2.4
83
17
218
45
3.5
2.5
82
17
215
32
3.3
87
13
3.3
166
88
65
35
180
85
68
32
179
68
73
27
233
18
92
7
232
33
88
13
220
25
89
10
Abbreviations: NSCLC, non–small-cell lung cancer; SCLC, small-cell lung cancer; ECOG, Eastern Cooperative Oncology Group; BPI, Brief Pain
Inventory; SRE, skeletal-related event.
*Twenty-eight days in a month.
3153
ZOLEDRONIC ACID FOR BONE METASTASES
Table 3.
Proportion of Patients Experiencing Individual Skeletal-Related Events by Treatment Group
Zoledronic Acid 4 mg
(n ⫽ 257)
Zoledronic Acid 8/4 mg
(n ⫽ 266)
Placebo
(n ⫽ 250)
Skeletal-Related Event
No. of
Patients
%
No. of
Patients
%
No. of
Patients
%
Radiation to bone
Pathologic fracture
Vertebral
Nonvertebral
Surgery to bone
Spinal cord compression
Hypercalcemia of malignancy
Any skeletal-related event
69
40
20
26
11
7
0
97
27
16
8
10
4
3
0
38
70
31
13
21
14
7
2
93
26
12
5
8
5
3
1
35
81
53
30
29
9
10
8
117
32
21
12
12
4
4
3
47
skeletal events (including HCM), 4 mg zoledronic acid significantly reduced the proportion of patients with an event as
compared with the placebo group (38% v 47%; P ⫽ .039).
Similarly, 35% of patients treated with 8/4 mg zoledronic acid
had an event (P ⫽ .006 compared with the placebo group). Table
3 summarizes the proportion of patients with each individual
type of SRE. The most common SREs were radiation to bone
and pathologic fracture. A treatment benefit was observed across
all event types; in particular, no patients treated with 4 mg
zoledronic acid developed HCM compared with 8 patients (3%)
in the placebo group (P ⫽ .004). Compared with the placebo
group, patients in the 8/4-mg group experienced significant
decreases in HCM (P ⫽ .044), pathologic fracture (P ⫽ .003),
and vertebral fracture (P ⫽ .004).
Zoledronic acid also significantly extended the median time to
first SRE by more than 2 months compared with placebo (Fig 1).
Median time to first SRE (excluding HCM) was 230 days for 4
mg zoledronic acid versus 163 days for placebo (P ⫽ .023);
median time to first SRE (including HCM) was 230 days versus
155 days for placebo (P ⫽ .007). When this analysis was
performed excluding HCM, and using only the first 700 enrolled
patients (planned enrollment), the results were similar (P ⫽
.020). A Cox regression stratified analysis adjusting for previous
SRE experience showed that this comparison remained statisti-
cally significant (P ⫽ .028). The median time to first event was
not reached for individual SREs. However, the time to first
pathologic fracture was significantly longer in patients treated
with 4 mg zoledronic acid compared with the placebo group
(first quartile, 238 v 161 days; P ⫽ .031). Likewise, the time to
first vertebral fracture and the time to first radiation therapy were
significantly longer (P ⫽ .05) in the 4-mg group. Because patient
survival in this study was short (approximately 6 months), time
to first SRE was also performed including death as an event.
Results were similar as reported earlier: for patients treated with
4 mg zoledronic acid, the median time to first event (excluding
HCM, including death) was 136 days versus 93 days for the
placebo group (P ⫽ .039). For each analysis, event rates were
similar in the 4-mg and 8/4-mg groups.
The skeletal morbidity rate for all events (SREs excluding
HCM) was lower among patients treated with either 4 mg
zoledronic acid (mean ⫾ SD, 2.24 ⫾ 9.12; P ⫽ .069) or 8/4 mg
zoledronic acid (mean ⫾ SD, 1.55 ⫾ 3.8; P ⫽ .005) compared
with the placebo group (mean ⫾ SD, 2.52 ⫾ 5.11). The skeletal
morbidity rate (the number of events per year; including HCM)
was significantly lower among patients treated with either 4 mg
zoledronic acid (mean ⫾ SD, 2.24 ⫾ 9.12; P ⫽ .017) or 8/4 mg
zoledronic acid (mean ⫾ SD, 1.59 ⫾ 3.8; P ⫽ .001) compared
with the placebo group (mean ⫾ SD, 2.73 ⫾ 5.29). The skeletal
morbidity rate for each type of SRE was lower in the zoledronic
acid treatment groups compared with the placebo group except
for surgery to bone and spinal cord compression.
A multiple event analysis using the Andersen-Gill approach
demonstrated a significant 27% risk reduction for multiple
events, in favor of 4 mg zoledronic acid (hazard ratio ⫽ 0.732;
Table 4. Hazard Ratio of Occurrence of SREs in Patients Treated With 4 mg
Zoledronic Acid Compared With Patients Treated With Placebo, Based on the
Multiple Event Analysis*
SRE (not including HCM)
Fig 1. Kaplan-Meier estimates of time to first skeletal-related event (not
including hypercalcemia of malignancy).
SRE (including HCM)
Stratum
Hazard
Ratio
Robust
P
Hazard
Ratio
Robust
P
Lung cancer
Other solid tumors
Total
0.729
0.737
0.732
.061
.136
.017
0.706
0.696
0.701
.036
.071
.006
Abbreviations: SRE, skeletal-related event; HCM, hypercalcemia of malignancy.
*Andersen-Gill method.
3154
P ⫽ .017; Table 4). The results were similar when HCM was
included in the analysis.
Substrata Analysis of SREs
Because the trial was powered for the primary end point,
subset analyses were not expected to detect statistically significant differences. Nevertheless, findings in both the NSCLC and
other solid tumor strata suggested a consistent treatment benefit
with respect to occurrence of SREs and time to first SRE
compared with the placebo group. The proportion of patients
with an SRE was not significantly different for patients in the
NSCLC stratum treated with 4 mg zoledronic acid versus
placebo (42% v 45%; P ⫽ .557); however, there was a trend
toward a longer time to first event (median 171 v 151 days; P ⫽
.188) for patients treated with 4 mg zoledronic acid. In the other
solid tumor stratum, 4 mg zoledronic acid substantially reduced
the proportion of patients with an SRE (33% v 43%; P ⫽ .110)
and extended the time to first event (median, 314 v 168 days;
P ⫽ .051) compared with placebo. Notably, the multiple event
analysis demonstrated a 27% reduction in the risk of skeletal
events in favor of 4 mg zoledronic acid among patients in both
the NSCLC cancer and other solid tumor strata, versus the
placebo group (Table 4). When patients were grouped according
to the radiologic appearance of their bone lesions, 4 mg
zoledronic acid demonstrated consistent reductions in SREs
among patients with osteolytic and osteoblastic bone metastases
(data not shown).
Pain, Analgesic Use, and ECOG Performance Status
Other efficacy end points included the change from baseline in
BPI composite pain score, analgesic score, and ECOG performance status. The mean BPI composite pain score increased
slightly from baseline to month 9 for all three treatment groups,
indicating increases in pain. However, the mean composite pain
score decreased among patients in the 4-mg zoledronic acid
group who had pain at baseline. Mean analgesic score and
ECOG performance status also increased from baseline to month
9 for all three treatment groups, indicating increases in analgesic
use and decreases in functional capacity due to progressive
disease. There were no statistically significant differences between zoledronic acid and placebo with respect to any of these
global quality-of-life outcomes. Changes in FACT-G scores
were also comparable between treatment groups.
Bone Lesion Response and Time to Progression of
Bone Lesions
Analysis of best radiographic bone lesion response at month 9
indicated a partial response in 8% of patients treated with 4 mg
zoledronic acid versus 4% of placebo-treated patients. Bone
lesions progressed in 33% and 36% of patients treated with 4 mg
zoledronic acid or placebo, respectively. The time to progression
of bone lesions was longer in patients treated with 4 mg
zoledronic acid (median, 145 days; P ⫽ .340) and in patients
treated with 8/4 mg zoledronic acid (median, 238 days; P ⫽
.009) compared with the placebo group (median, 109 days).
ROSEN ET AL
Bone Markers
All markers of bone metabolism, including N-telopeptide,
pyridinoline, and deoxypyridinoline creatinine ratios, as well as
serum bone alkaline phosphatase, decreased from baseline to
study end in patients treated with zoledronic acid. Suppression of
bone markers was similar in the 4-mg and 8/4-mg groups, and
differences in the median percent change from baseline between
the zoledronic acid treatment groups and the placebo group were
statistically significant at each time point. At study end, the
N-telopeptide to creatinine ratio was reduced 55% below baseline in patients treated with 4 mg zoledronic acid, compared with
an 11% increase in the placebo group (P ⬍ .001). Similar results
were observed with other bone markers, including pyridinoline
to creatinine ratio (P ⬍ .001) and deoxypyridinoline to creatinine
ratio (P ⬍ .001). Parathyroid hormone was increased from
baseline in all treatment groups, though patients treated with
zoledronic acid experienced a greater increase in parathyroid
hormone compared with the placebo group. Alkaline phosphatase, a marker for bone formation, decreased from baseline by
12% in patients treated with 4 mg zoledronic acid, compared
with a 2% increase in the placebo group (P ⬍ .01).
Time to Disease Progression and Overall Survival
The median time to overall disease progression was 89 days in
patients treated with 4 mg zoledronic acid, compared with 84
days in patients treated with placebo (P ⫽ .117). The median
time to death was similar in both treatment groups, with a
median of 203 days for patients treated with 4 mg zoledronic
acid, compared with 183 days for the placebo group (P ⫽ .623).
Safety
The most commonly reported adverse events (all grades) in all
treatment groups were bone pain, nausea, anemia, vomiting,
constipation, dyspnea, and fatigue (Table 5). The proportion of
patients having nausea, vomiting, and dyspnea was higher in the
4-mg zoledronic acid treatment group compared with the placebo group. The proportion of patients experiencing bone pain,
however, was higher in the placebo group compared with either
zoledronic acid treatment group. Serious adverse events affected
similar proportions of patients in all treatment groups. The most
frequently reported serious adverse events, regardless of relation
to study drug, were anemia, dehydration, aggravated malignant
neoplasm, and dyspnea, and these were similar across the
treatment groups.
Renal adverse events, which are known to be associated with
intravenous (IV) bisphosphonates, were reviewed in greater
detail. Decreased renal function was defined as a change from
baseline serum creatinine of ⱖ 0.5 mg/dL for patients with
normal baseline serum creatinine and ⱖ 1.0 mg/dL for patients
with abnormal baseline serum creatinine or at least two times
baseline value. Before the implementation of the 15-minute
infusion amendment, the proportion of patients with decreased
renal function was substantially higher in the zoledronic acid
treatment groups compared with the placebo group (Table 6),
with a hazard ratio of 3.8 by Kaplan-Meier analysis. However,
3155
ZOLEDRONIC ACID FOR BONE METASTASES
Most Frequently Reported Adverse Events (all grades) in > 15% of Patients by Treatment Group Regardless of
Relationship to Study Drug
Table 5.
Zoledronic Acid 4 mg
(n ⫽ 254)
Zoledronic Acid 8/4 mg
(n ⫽ 265)
Placebo
(n ⫽ 247)
Adverse Event
No. of
Patients
%
No. of
Patients
%
No. of
Patients
%
Bone pain
Nausea
Anemia
Vomiting
Constipation
Dyspnea
Fatigue
Pyrexia
Weakness
Anorexia
Edema of lower limb
Aggravated malignant neoplasm
Cough
Diarrhea
Headache
Insomnia
Dehydration
129
116
94
91
85
83
79
67
66
58
56
54
47
43
42
42
40
51
46
37
36
34
33
31
26
26
23
22
21
19
17
17
17
16
130
106
82
83
76
90
78
70
67
60
53
67
44
48
36
38
48
49
40
31
31
29
34
29
26
25
23
20
25
17
18
14
14
18
145
83
82
71
89
65
72
56
65
62
49
56
38
44
26
30
41
59
34
33
29
36
26
29
23
26
25
20
23
15
18
11
12
17
after the implementation of the 15-minute infusion-time amendment, the proportion of patients with decreased renal function
was not significantly different between the 4-mg zoledronic acid
and placebo groups (10.9% v 6.7%). Notably, for patients
randomized after the infusion-time amendment (n ⫽ 578), there
was no significant difference in time to first episode of decreased
renal function between the 4-mg zoledronic acid and placebo
groups (hazard ratio, 1.57; P ⫽ .228). Therefore, the infusiontime amendment substantially reduced the excess risk of increased serum creatinine compared with placebo.
DISCUSSION
In this trial, zoledronic acid (at the recommended dose of 4 mg
via a 15-minute infusion every 3 weeks in addition to standard
antineoplastic therapy) demonstrated a consistent reduction of
skeletal morbidity across multiple end points compared with
Table 6.
placebo in patients with lung cancer and a variety of other solid
tumors, though the primary end point (proportion of patients
with an SRE at 9 months) did not reach statistical significance.
However, the end-of-study difference in the proportion of
patients with an SRE, only provides a snapshot of the true
difference because of the shorter-than-expected survival in both
groups of patients. Importantly, analysis of time to first SRE
showed an early and continued separation of the event curves,
and the median time to the first event was significantly extended
by more than 2 months in patients treated with zoledronic acid.
In this population of patients with a median survival of only 6
months, time to first SRE is a meaningful measure of treatment
effect because it accounts for the timing of events and patient
discontinuations. Only approximately one fourth of the patients
in each treatment group completed the study, because of rapid
disease progression in this end-stage population.
Proportion of Patients With Serum Creatinine Increase by Baseline Serum Creatinine and Treatment Group
Zoledronic Acid 4 mg
Baseline Serum Creatinine
Prior to protocol amendment
Normal*
Abnormal†
Total
After protocol amendment
Normal*
Abnormal†
Total
No. of
Patients
Zoledronic Acid 8/4 mg
%
No. of
Patients
7/55
3/6
10/61
13
50
16.4
17/154
1/11
18/165
11
9
10.9
Placebo
%
No. of
Patients
%
5/47
2/8
7/55
11
25
12.7
3/50
0/4
3/54
6
0
5.6
19/160
2/21
21/181
12
10
11.6
10/143
1/20
11/163
7
5
6.7
NOTE. “Prior to” and “After protocol amendment” indicates those patients treated before or after, respectively, the amendment to
15-minute infusion of zoledronic acid.
*Normal baseline serum creatinine was defined as ⬍ 1.4 mg/dL, and serum creatinine increase was defined as a change from
baseline ⱖ 0.5 mg/dL or at least two times baseline value.
†Abnormal baseline serum creatinine was defined as ⱖ 1.4 mg/dL, and serum creatinine increase was defined as a change from
baseline ⱖ 1.0 mg/dL or at least two times baseline value.
3156
ROSEN ET AL
The proportion of patients with an SRE and time to first SRE
are both conservative end points, used in previous multicenter
studies of other bisphosphonates.9 However, the skeletal morbidity rate and multiple event analysis may more accurately
reflect the degree of skeletal morbidity commonly seen in these
patients because they capture information on all SREs occurring
after the first event. In this trial, the skeletal morbidity rate was
significantly lowered in patients treated with zoledronic acid
compared with the placebo group when HCM was included in
the analysis. Moreover, the multiple event analysis demonstrated a significant and consistent reduction in the risk of
skeletal complications in the overall patient population and in
both stratification groups. Although not reported here, two
other multiple event analysis methods (Wei-Lin-Weissfeld,
and Prentice, Williams, and Peterson) confirm these results.10,11 These results are particularly striking given the
heterogeneous nature of the patient population and the advanced stage of disease. Moreover, the median duration of
exposure to zoledronic acid was only approximately 4
months. Aside from all these statistical considerations, the
weight of the evidence from all end points suggests the
clinical benefit of zoledronic acid.
Markers of bone turnover were all significantly suppressed in
patients treated with zoledronic acid compared with placebo,
confirming the pharmacologic activity on surrogate bone markers. There is no objective evidence, however, based on changes
in bone resorption markers or time to event analyses, that 8 mg
zoledronic acid is more effective than 4 mg.
This is the first large randomized trial to demonstrate a
treatment benefit for bisphosphonate therapy in patients with
lung cancer and other solid tumors. The true clinical impact
of this therapy is difficult to measure in terms of the
improved quality of life for patients who are able to maintain
their independence longer and suffer fewer debilitating and
painful skeletal complications. Pathologic fractures can be
particularly problematic, often requiring hospitalization and
surgical intervention.
Zoledronic acid (4 mg via 15-minute infusion every 3 weeks)
was well tolerated. The clinical adverse-event profile for patients
treated with zoledronic acid was similar to that of patients treated
with placebo and was consistent with that of other IV bisphosphonates.12,13 Adverse events with a higher incidence in the
zoledronic acid groups, compared with the placebo group,
included nausea, anemia, pyrexia, vomiting, and dyspnea. However, these events were primarily mild to moderate in severity.
Furthermore, there was no difference in the incidence of reported
serious adverse events between treatment groups.
Although bisphosphonates are generally well tolerated, impaired renal function has been associated with the IV administration of these drugs as a class.14 The renal safety profile of 4
mg zoledronic acid (via 15-minute infusion) was consistent with
that of other IV bisphosphonates. Among patients receiving
15-minute infusions, there was no significant difference between
the 4-mg zoledronic acid and placebo groups in time to first
episode of decreased renal function, with a hazard ratio of 1.57.
Therefore, infusion of 4 mg zoledronic acid via 15-minute
infusion is associated with only a slightly greater risk of
increased serum creatinine compared with placebo. In a large
phase III trial in patients with breast cancer and multiple
myeloma, 4 mg zoledronic acid via 15-minute infusion was
associated with a similar risk of serum creatinine increase
compared with 90 mg pamidronate disodium via 2-hour infusion
(risk ratio, 1.0).5 The 8-mg dose of zoledronic acid, however, has
been associated with an increased incidence of renal function
deterioration, even when administered via 15-minute infusion,
and should not be used.
In summary, zoledronic acid has demonstrated clinical utility
in the treatment of HCM3 and bone metastases in patients with
breast cancer or multiple myeloma5 and prostate cancer.15 The
current study is the first to demonstrate the efficacy of a
bisphosphonate across multiple end points of clinical significance in patients with bone metastases secondary to lung cancer
and other solid tumors. The results of this trial support an
expanded role for zoledronic acid in the treatment of patients
with solid tumors and bone metastases.
ACKNOWLEDGMENT
The acknowledgment is included in the full text version of this article only, available on-line at www.jco.org.
It is not included in the PDF version.
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